Transcranial Magnetic Resonance guided Histotripsy (tcMRgHt) Project Summary The goal of this proposal is to develop the first integrated tcMRgHt system for treatment of brain tumors. Approximately 256,000 new patients are diagnosed with primary brain tumor annually worldwide, and many more patients are diagnosed with brain metastases. The current clinical treatment for brain tumors is a highly invasive surgery. The five-year survival rate is only 33% with many surviving patients suffering from cognitive deficits. Transcranial magnetic resonance guided focused ultrasound (tcMRgFUS) has been investigated as a noninvasive ablation method in the brain. However, due to the overheating of the skull, tcMRgFUS cannot treat a target volume >1 cm diameter in the brain or locations within 2 cm from the skull surface, rendering inoperable up to ~90% of the cortex regions where brain tumors often reside. We hypothesize that transcranial MR guided histotripsy (tcMRgHt) can overcome the treatment location and volume limitations of tcMRgFUS and provide a non-invasive ablation technique to improve the treatment of brain tumors. Using microsecond-length, high-amplitude ultrasound pulses applied from outside the skull, cavitation can be precisely generated to disrupt cells within the targeted brain region. The heating to the skull and surrounding tissue can be avoided by using a very low duty cycle (<0.1%). Our preliminary data show that histotripsy applied through excised human skulls was used to ablate a wide range of locations and brain volumes inside the skull, while keeping the temperature increase in the skull under 4C. Although the feasibility of transcranial histotripsy and MRI guidance has been shown separately, developing and building an integrated tcMRgHt system is a substantial technical challenge. We propose the following three specific aims. 1) Design and construct an integrated tcMRgHt system. 2) Develop and optimize specialized RF pulse sequences for MRI guidance of tcMRgHt. 3) Validate the performance of the tcMRgHt system in ex vivo brain phantom and human cadaver. An integrated tcMRgHt system that can noninvasively treat a wide range of locations and volumes in the brain and validated in human cadavers would be a critical milestone to advance this promising technology for future clinical translation for treatment of brain tumors.